Enhanced clinical outcomes with radiotherapy in diagnostically challenging intracranial plasmacytomas: Analysis of 190 cases

Abstract Background Intracranial plasmacytomas are rare tumors arising from plasma cells with approximately half of the cases progressing to multiple myeloma (MM). However, there is a lack of comprehensive clinical cohort analysis on the clinical and pathological features, progression, and outcomes of intracranial plasmacytomas. Methods A retrospective analysis of 190 cases was conducted, combining data from 38 cases in a single institution and 152 cases from the literature. Patient demographics, clinical presentations, tumor locations, imaging features, surgical treatments, and follow‐up outcomes were collected and analyzed. Survival analysis and Cox regression analysis were performed to identify prognostic factors. Results A total of 190 intracranial plasmacytoma patients with an average age of 55.4 years were included in the study. The preoperative misdiagnosis ratio was high at 55.3%, and 59.7% of the tumors affected the calvaria convexity, compared to 40.3% located at the skull base. Resection and biopsy were achieved in 72.4% and 27.6% patients, respectively. Among them, 34.2% (65/190) of patients were initially diagnosed with MM with intracranial plasmacytoma as their first presentation (MM‐IPFP), while 63.2% (120/190) of patients were diagnosed with solitary intracranial plasmacytoma (SIP), including 61 extramedullary plasmacytomas and 59 solitary bone plasmacytomas. In the SIP group, 22.4% (24/107) of patients experienced disease progression leading to the development of MM during a median follow‐up time of 42.6 months (range 1–230 months). Multivariate analysis unveiled that radiotherapy (HR, 0.05; 95% CI, 0.00–0.87; p = 0.04), not surgery, was a protective prognostic factor for overall survival in MM‐IPFP patients. Comparison between the SIP progression group and non‐progression group revealed a significant difference of Ki‐67 index (non‐progression vs. SIP progression, 8.82% ± 7.03 vs. 16.5% ± 10.5, p < 0.05). AUC analysis determined that a cutoff value of 9.0% was the best predictor of SIP progression, with an area under the curve of 0.712. Conclusions This retrospective clinical analysis highlights the potential role of radiotherapy, rather than surgical resection, in improving the outcomes of intracranial plasmacytoma. Additionally, the Ki‐67 index is identified as a valuable marker for predicting disease progression. This would provide some evidence for the paradigm of diagnosis and treatment modalities for intracranial plasmacytomas from the large cohort.

Intracranial plasmacytomas are uncommon tumors characterized by an abnormal proliferation of clonal plasma cells that secrete immunoglobulins.These neoplasms can manifest as solitary bone plasmacytoma (SBP), extramedullary plasmacytoma (EMP), or multiple lesions. 1,2Nearly 5% of patients with multiple myeloma (MM) present an initial diagnosis of solitary plasmacytoma, with EMP commonly occurring in the head and neck and SBP affecting in the axial skeleton without systemic involvement. 3Solitary intracranial plasmacytoma (SIP) generally has a favorable prognosis, with a 5-year overall survival rate of 76.1%. 4 However, the high misdiagnosis rate and susceptibility of progression to MM pose significant challenges in the management and treatment of this rare disease.Intracranial plasmacytoma commonly involves the skull base, meninges, and brain but lacks specific imaging features.Approximately 25% of solitary plasmacytoma cases progress to MM within 5 years, 4 with a median time to progression of 10.5 months for SBP and 18.6 months for EMP. 5 Systemic examinations are necessary to monitor disease progression, as prognosis significantly worsens when accompanied by MM, resulting in a median survival time of merely 6.7 months. 4Early identification of patients with plasmacytomas and those at risk of progressing to MM is crucial for appropriate management.
The treatment of intracranial plasmacytoma requires multidisciplinary guidance, particularly when a diagnosed of MM is combined with plasmacytoma.The benefit of surgery in improving outcomes remains controversial and is recommended primarily for tumors causing structural instability or neurological compromise. 4,6For solitary plasmacytomas, radiotherapy (RT) is the preferred intervention, reducing local relapse rates from 60% to 12%. 6,7However, the optimal radiation dose for treatment remains uncertain and should be judiciously adjusted for patients with progression to MM.The current standard chemotherapy (CMT) regimen for newly diagnosed MM involves dexamethasone, proteasome inhibitors (bortezomib or carfilzomib), and lenalidomide.The combination improves the rate of complete response to 30% and prepares patients for was high at 55.3%, and 59.7% of the tumors affected the calvaria convexity, compared to 40.3% located at the skull base.Resection and biopsy were achieved in 72.4% and 27.6% patients, respectively.Among them, 34.2% (65/190) of patients were initially diagnosed with MM with intracranial plasmacytoma as their first presentation (MM-IPFP), while 63.2% (120/190) of patients were diagnosed with solitary intracranial plasmacytoma (SIP), including 61 extramedullary plasmacytomas and 59 solitary bone plasmacytomas.In the SIP group, 22.4% (24/107) of patients experienced disease progression leading to the development of MM during a median follow-up time of 42.6 months (range 1-230 months).Multivariate analysis unveiled that radiotherapy (HR, 0.05; 95% CI, 0.00-0.87;p = 0.04), not surgery, was a protective prognostic factor for overall survival in MM-IPFP patients.Comparison between the SIP progression group and non-progression group revealed a significant difference of Ki-67 index (non-progression vs. SIP progression, 8.82% ± 7.03 vs. 16.5% ± 10.5, p < 0.05).AUC analysis determined that a cutoff value of 9.0% was the best predictor of SIP progression, with an area under the curve of 0.712.

Conclusions:
This retrospective clinical analysis highlights the potential role of radiotherapy, rather than surgical resection, in improving the outcomes of intracranial plasmacytoma.Additionally, the Ki-67 index is identified as a valuable marker for predicting disease progression.This would provide some evidence for the paradigm of diagnosis and treatment modalities for intracranial plasmacytomas from the large cohort.autologous hematopoietic cell transplant. 8Adjuvant CMT has also demonstrated benefits in preventing the evolution of SBP to MM. 9 Meanwhile, novel immunotherapy options such as chimeric antigen receptor T-cell therapy 10 and bispecific antibodies 11 offer promising approaches for clinical trials.Understanding molecular events including cytogenetic abnormalities correlated with treatment response, 12 will further facilitate the implementation of individualized modalities to optimize patient outcomes.
In this retrospective study, we analyzed the characteristics and outcomes of 190 patients with intracranial plasmacytoma, combining data from 38 patients at our center and 152 patients from a literature review.The aim is to identify clinical characteristics and prognostic factors associated with patient outcomes and determine the best treatment and post-operative regime for this population.

| Retrospective clinical cohort design and data collection
Medical data from patients admitted to the Department of Neurosurgery, Huashan Hospital, between January 1st, 2002, and October 31st, 2022, was screened.The inclusion criteria were as follows: (1) patients aged >18 and < 80 years old; (2) histopathology confirmation of intracranial plasmacytomas; (3) availability of complete clinical and pathological data; and (4) availability of survival and follow-up data.The exclusion criteria included: (1) lack of available clinical data; (2) absence of histopathological confirmation; (3) difficulty in patients or family to cooperation with follow-up; and (4) preexisting diagnosis of MM prior to surgery.Patients diagnosed with MM during their post-operation hospitalization period by bone marrow biopsy were still included in this study and classified as patients with MM with intracranial plasmacytoma as the first presentation (MM-IPFP).A total of 38 patients were enrolled in this study.This cohort research was approved by the Institutional Review Board of the hospital (approval ID: 2015-256) and was conducted in accordance with the Helsinki Declaration.Written informed consent was obtained from all patients.This work was reported in line with the Strengthening the Reporting of Cohort Studies in Surgery (STROCSS) criteria and was retrospectively registered at https:// www.chictr.org.cn.Electronic medical records were used to collect clinical data, including basic information, clinical symptoms, imaging findings, surgical findings and outcomes, pathological results, and clinical outcomes.

| Histopathological diagnosis and immunohistochemistry
The tumor tissue specimens were fixed in a 10% formalin solution, followed by embedding in paraffin and staining with hematoxylin-eosin.The diagnosis of solitary plasmacytoma and MM was determined based on the established International Myeloma Working Group (IMWG) criteria. 2For immunohistochemistry, a representative tissue block was selected and subjected to the avidinbiotin complex horseradish-peroxidase method.Primary antibodies against CD138 (Abcam, ab130405), kappa light chain (Abcam, ab227654), lambda light chain (Abcam, ab195573), and Ki-67 (Abcam, ab15580) were applied according to the manufacturer's instructions.Two pathologists independently evaluated all stained sections without any knowledge of the corresponding clinical data.In cases of discordance, the staining results were reviewed by the observers until a consensus was reached.

| Clinical management of intracranial plasmacytoma
Patients diagnosed with intracranial plasmacytoma were managed according to a multidisciplinary approach.The treatment strategy involved a combination of surgical intervention, RT, and CMT.Surgical resection was considered for accessible and resectable lesions, aiming to achieve maximal tumor removal while preserving neurological function.The extent of tumor resection was classified as total resection (no residual tumor), subtotal resection (more than 90% of tumor removed), partial resection (less than 90% of tumor removed), and biopsy based on the neurosurgeon's intraoperative estimate.RT was employed as a primary treatment modality or as an adjuvant therapy postsurgery.Briefly, a total of fractionated 30-60 Gy irradiation was conducted for solitary plasmacytoma and low-dose RT (8 Gy × 1 fraction or 10-30 Gy in 2.0-3.0Gy fractions) for palliation in patients with MM.Chemotherapy was administered in cases of advanced or disseminated disease according to the National Comprehensive Cancer Network Guidelines for MM 6 based on individual patient characteristics and disease factors.

| Follow-up
Following the operation and initial treatments, two neurosurgeons completed the follow-up to monitor disease progression and assess treatment response at specific time intervals.The focus of the follow-up included evaluating post-operative chief complaints, disease progression, recurrence, overall survival, and the management of chemotherapy and radiotherapy.Additionally, the diagnosis of MM was closely monitored during the follow-up period.Tumor progression included tumor recurrence indicated by a notable increase in imaging findings and progression to MM, defined as bone marrow plasmacytosis ≥10% or when plasmacytoma presented with multiple lesions according to IMWG criteria.Diagnosis of disease progression involved a multidisciplinary team including hematologists, radiologists, and pathologists from our hospital.Additional follow-ups were scheduled in cases of deteriorating patient conditions after the last contact or treatment.

| Statistical analysis
Statistical analyses were performed on the cases from our center (n = 38) and prior literature (n = 152).Survival outcomes were summarized using the Kaplan-Meier method, and the log-rank test was employed to assess the differences between the survival curves.Univariate and multivariate analyses were conducted using Cox's proportional hazards regression model to explore the associations between clinical and pathological characteristics and patient survival.Fisher's exact test was used for nominal variables.Hazard ratios were reported with 95% CIs.Statistical significance was defined as p < 0.05.All statistical tests were two-sided.All the statistical analyses were conducted using the R programing language (version 4.1.0.) and Prism 9.0.

| The diverse clinical and radiological manifestation of intracranial plasmacytoma would lead to high ratio of pre-operative misdiagnosis
Totally, 190 patients with intracranial plasmacytoma including 38 from our center and 152 available from literature were combined for analysis, as the evaluation was described in the flow chart (Figure 1).The gender distribution is evenly balanced with 98 males and 90 females (54.1% vs. 47.9%,p = 0.51), and the mean age was 55.8 ± 13.1-year-old (range 24-84), as shown in Table 1.The most common presenting symptoms reported were F I G U R E 1 Prisma flow diagram illustrating the process of literature review.A total of 247 articles were identified through electronic database searches.After removing articles through title screening, 232 articles remained.After writing language and article retrieval methods screening, 204 articles were included for full-text assessment.Finally, 152 cases from 77 case reports and 17 case series met the inclusion criteria and were included in this systematic review.2).It can be distributed in the left side (34.0%), right side (35.8%), and mid (30.2%).There were no significant differences observed between the Huashan cohort and the literature cohort, except for their presenting symptoms (p = 0.008).The Huashan cohort exhibited a higher incidence of blurred vision (34.2% vs. 21.7%,p = 0.11), while the literature review cohort had a greater prevalence of oculomotor nerve paralysis (10.5% vs. 26.6%,p = 0.037).

| Neurosurgical management and follow up
Among the 127 patients with documented surgical outcomes, the operation performed consisted of total removal (46.2%), subtotal removal (20.3%), partial removal (15.8%), and biopsy (27.6%).Notably, a significant difference was observed between the Huashan cohort and the literature review cohort, as shown in Table .1.The choice of surgical approach mainly depended on tumor location and included microsurgery and endoscopic surgery.In the Huashan cohort, one patient with a left maxillary sinus lesion underwent left paranasal sinus biopsy.Among the 20 craniotomies, seven patients had their bone flap reset, while 13 patients had their bone flap discarded.Of these, 11 patients underwent onestage operation with titanium plate shaping.For the 12 trans-sphenoid surgeries, none of them mentioned cerebrospinal fluid leakage.Notably, one case in the sellar region experienced excessive intraoperative blood loss and symptoms of shock, prompting the surgeons to pause the operation and control the blood pressure.
The most common gross characteristics of intracranial plasmacytoma were hyperemic (38.9%), bone invasion (88.9%), and dura invasion (69.4%).Following postoperative bone marrow biopsy and comprehensive systemic assessment, 65 patients (35.3%) were identified as having MM, presenting initially with intracranial plasmacytoma (MM-IPFP).Sixty cases (32.6%) were diagnosed as EMP, while 59 cases (32.1%) were classified as SBP.Pathological results showed a wide distribution of Ki-67 values ranging from 1% to 90%, with a median of 19.9 ± 20.1% (n = 72).Immunohistochemistry showed that all tumors (n = 90) were positive for CD138.Monoclonal kappa and lambda light chain expression were identified in 73 (68.2%) and 46 (43.0%) patients, respectively.In summary, patients with intracranial plasmacytoma lack specific clinical features at presentation and during intraoperative evaluation.Follow-up data were available for 155 cases, with a mean follow-up period of 42.6 months (range 1-230).At the time of the latest follow-up evaluation, 127 (81.9%) patients were still alive, with a median survival of 141 months.There was no significant difference between the Huashan cohort and the literature review cohort (141 months vs. not determined, p = 0.3).Until the last follow-up, 24 (22.4%)patients with SIP progressed to MM.Combined RT and CMT were used in 60 (31.7%) patients.Additionally, 58 (30.7%) patients and 34 (18.0%)patients received RT alone and CMT alone, respectively, while 20 (10.6%) patients did not receive any form of treatment.

| Radiotherapy not surgery would improve the prognosis of MM-IPFP
To investigate the prognostic value of clinicopathological features in intracranial plasmacytomas, survival and Cox analysis were conducted on a combined cohort from our center and literature reviews.A total of 155 patients with an average follow-up period of 41.7 months were included.SIP demonstrated significantly improved survival compared to MM-IPFP by Kaplan-Meier curves (SIP vs. MM-IPFP, mean time not determined vs. 53 months, n = 107 vs. 48, p < 0.05, Figure 3A).Separate analyses were performed for the MM-IPFP (Figure 3) and SIP (Figure 4) groups, evaluating general patient conditions, surgery outcomes, tumor dimensions and locations, pathological features, and the effects of post-operation management on survival.For the MM-IPFP group, univariate Cox analysis revealed that only RT (HR, 0.193; 95% CI, 0.052-0.712;p = 0.0135) was a risk factor for the survival (Table .2).In the SIP group, univariate Cox analysis identified age (HR, 1.07; 95% CI, 1.01-1.13;p = 0.0195) and CMT (HR, 3.76; 95% CI, 1.25-11.3;p = 0.0188) as risk factors for survival (Table .3).Tumor dimension (HR, 2.79; 95% CI, 0.823-9.48;p = 0.0995) was marginally associated with survival.Furthermore, we investigated the effects of clinicopathologic factors on survival.
The effects of clinicopathological factors on survival were further investigated.For the MM-IPFP group, the Kaplan Meier Curve revealed that patients who received post-operation RT had significantly longer survival compared to those who did not (with RT vs. without RT, median survival 71 months vs. 37 months, n = 25 vs. 23, p < 0.05, Figure 3D).While in the SIP group, patients who underwent post-operation CMT had a poorer prognosis compared to those without CMT (n = 38 vs. 64, p < 0.05, Figure 4D).Although not statistically significant, a trend towards prolonged survival was observed with a low Ki-67 index in the MM-IPFP group (Ki67 < 10% vs. Ki67 ≥ 10%, median survival 72 vs. 38 months, n = 7 vs.21 p = 0.1; Figure 3C) and with smaller tumor dimensions in the SIP group (dimension<5 cm vs. dimension≥5 cm, n = 42 vs.41 p = 0.088; Figure 4I).Gender, surgical strategy, tumor locations, and light chain staining did not show a significant difference in survival for both the MM-IPFP and SP groups (Figure 3B-I and Figure 4A-I).Further multivariate analysis indicated that only RT (HR, 0.05; 95% CI, 0.00-0.87;p = 0.04, Figure 3J) was significantly associated with positive prognosis in MM-IPFP, while progression to MM (HR, 4.86; 95% CI, 1.11-21.20;p = 0.04, Figure 4J) was significantly associated with poor prognosis in SIP.
3.4 | Ki-67 index could predict the progression of SIP to MM Progression to MM and recurrence are milestone events in the progression of SIP.We included 94 patients with complete follow-up of more than 6 months after surgery for analysis (Table .4) and divided them into the SIP with or without progression groups based on the IMWG criteria. 2here is a significant difference in survival between the progression group and the SIP group (progression vs. SIP, median survival 141 months vs. not determined, n = 36 vs. 56, p = 0.022; Figure 4A).Further, we found that SBP had a similar time interval of progression (SBP vs. EMP, mean time 22.2 months vs. 12.7 months, n = 25 vs. 13, p = 0.17, Figure 5B) and a significantly higher proportion of progression (SBP vs. EMP, n = 52.1% vs. 28.3%,p = 0.02, Figure 5C) compared to EMP.The impacts of progression were further investigated through a comparative analysis between the two groups.A significant correlation between post-operative treatment and progression was observed, as the progression group had a significant higher percentage of patients receiving RT (progression vs. SIP, 86.8% vs. 64.8%,n = 38 vs. 54, p = 0.03, Figure 5D) and CMT (progression vs. NPSIP, 73.0% vs. 21.2%,n = 37 vs. 52, p < 0.0001, Figure 5E) compared to the SIP group.Among the other factors explored, only the pathology Ki-67 index showed a significant difference (p = 0.018, Figure 5F).The mean Ki-67 value of SIP group was 8.82% ± 7.03 (n = 23, range 1%-25%), while the mean Ki-67 value of progression group was 16.5% ± 10.5 (n = 12, range 1-30%).Using ROC curve analysis, we determined that a Ki-67 index of 9.0% was the optimal cutoff value for predicting progression of SIP, with an area under the curve of 0.712 (Figure 5G).Additionally, there was a slight predominance of older age (57.2 ± 10.7 vs. 52.9± 13.7 years, progression vs. SIP, n = 38 vs. 56, p = 0.11), a higher percentage of females (62.2% vs. 41.1% female percentage, progression vs. SIP, n = 38 vs. 56, p = 0.15) and greater tumor dimension (58.1% vs. 53.8%≥5 cm percentage, progression vs. SIP, n = 31 vs. 42, p = 0.10) in the progression group.However, no significant differences were observed in surgical outcomes (84.2% vs. 88.9%resection percentage, progression vs. SIP, n = 38 vs. 54, p = 0.54) or tumor location (71.1% vs. 58.9%skull base percentage, progression vs. SIP, n = 38 vs. 56, p = 0.28) between the two groups.Plasmacytomas are characterized by the abnormal proliferation of clonal, immunoglobulin-secreting plasma cells.Typically, they manifest as localized collections of plasma tumor cells and rarely involve intracranial regions. 1 Through a retrospective analysis of 190 cases, we found that intracranial plasmacytomas tend to occur with high frequency on the calvaria convexity, particularly the frontal lobe and skull base regions.Long-term survival is contingent upon post-operative management of RT for MM-IPFP.Progression to MM is a poor prognostic factor for SIP, and Ki-67 index shows promise as a candidate for predicting the possibility of progression from SIP to MM.
Intracranial plasmacytomas often present as lesions with bone erosion and an abundant blood supply, which can be revealed through imaging techniques such as CT bone window and MRI enhancement and further confirmed by intra-operation situation and pathology. 4wever, preoperative diagnosis of intracranial plasmacytomas remains challenging due to the lack of obvious radiological characteristics, which can hinder treatment planning and precise sampling.For lesions located on the calvaria convexity, the most common misdiagnosis was meningioma because the base of plasmacytoma located on dural may be mistaken for dural tail sign.Two features can help distinguish between plasmacytoma and meningioma.Firstly, plasmacytomas can penetrate the skull bone and invade the galea aponeurotica.Secondly, plasmacytomas usually lack calcification compared to meningiomas.In the sellar region, plasmacytomas are frequently misdiagnosed as pituitary adenomas due to the similar radiology and symptoms related to vision.However, plasmacytomas tend to cause earlier bone erosion and neurology deficits, exhibiting fewer endocrine symptoms compared to pituitary adenomas.For plasmacytomas in the skull base, the most common misdiagnosis includes chordomas, followed by meningiomas, paragangliomas, metastasis, and inflammatory The bold values in the 'p-value' column represented data points that have reached statistical significance.
conditions.Histopathological examination including CD138 positivity and immunoglobulin light chain is required for a definitive diagnosis.
In cases where plasmacytomas are misdiagnosed as other intracranial lesion preoperatively, surgery can provide the pathological confirmation and symptom relief.In our series, surgical treatment was common with a total removal rate 43.2%.The biopsy rate was lower at 8.1%, compared with 35.6% reported in literature reviews.This discrepancy may be partially attributed to the challenges in preoperative diagnosis.Survival analysis revealed no significant difference between groups with surgical strategies, which may be due in part to the high sensitivity of plasmacytomas to RT.Previous studies identified that local control rates of 80-100% can be achieved by RT, making it the treatment of choice for preventing progression to MM and recurrence. 13The recommended clinical radiation dose ranged between 3000 cGy and 5400 cGy. 14MT regimens for plasmacytomas include the combination of lenalidomide, bortezomib, and dexamethasone for standard-risk patients and carfilzomib, lenalidomide, and dexamethasone for high-risk patients, followed by a proteasome-inhibitor-based regimen for maintenance therapy.Other regimens, including cyclophosphamide or thalidomide, are used in patients with acute renal failure. 15However, the impact of CMT in the treatment of solitary plasmacytoma remains a contentious topic with conflicting findings in the literature.Similarly to the study by Ma et al., 4 we found that SIP patients who received CMT had significantly shorter survival compared to those without CMT.However, upon conducting multivariate analysis, we observed that CMT was not an independent prognostic factor, and progression to MM may play a more significant role in contributing to the poorer prognosis.Mignot et al. reported improved outcomes when using CMT with concurrent lenalidomidedexamethasone compared to radiation therapy alone. 16urthermore, other studies have suggested that chemotherapy is associated with a decreased risk of disease progression. 9Recently, autologous stem cell transplantation (ASCT) has emerged as a significant treatment option for patients with MM.Studies have showed ASCT can significantly prolong progression-free survival, 17 and improves median survival time by approximately 1 year. 2 For patients with initial plasmacytoma, ASCT is also recommended for eligible transplant patients and should be taken into consideration at the first relapse. 2,18rogression to MM is a milestone event of intracranial plasmacytomas.Previous studies have reported a 5-year disease progression-free survival was 52.9%. 4 Our investigation revealed that in a 3.3-year follow-up period, 9.3% patients with EMP and 35.8% patients with SBP progressed to MM.We also found a tremendous difference in post-operative survival between patients with SIP who  The limited understanding of the molecular mechanisms underlying intracranial plasmacytomas highlights the need for further research.We compiled the existing literature on molecular events related to intracranial plasmacytomas (Table 5) and identified a case of EMP in which 13q14 deletion and p53 deletion were detected through fluorescence in situ hybridization. 19This patient experienced disease progression to MM 1 year after surgery confirmed by the bone marrow biopsy.Additionally, in 5 cases of MM-IPFP, cytogenetic abnormalities including 1q gain, 17p deletion, monosomy 13 and 14, t(11;14) and t (11;14) were detected, which have been recognized as high-risk events of MM in the updated IMWG criteria. 2ecent studies have also identified genetic alterations in KRAS, NRAS, and BRAF that substantially contribute to the progression of EMP, presenting potential avenues for targeted therapeutic interventions. 20Otherwise, the acquisition of hyperdiploidy or translocations involving immunoglobulin heavy chain gene loci are initiating events driving the development of MM, widely presents in the precursor states of monoclonal gammopathy of undetermined significance and smoldering MM.As precursor states progress to MM, the frequency of genetic abnormalities including copy number variations, secondary translocations, and somatic mutations increases, leading to dysregulation of cell cycle control and subsequent disease progression. 21Whether tumor cells undergo clonal selection under treatment-induced or environmental stress during the progression from intracranial plasmacytoma to MM needs further research.
Intracranial plasmacytoma is an exceedingly rare lesion that poses a diagnostic challenge prior to surgery.The prognosis of intracranial plasmacytoma is generally favorable, unless there is progression leading to the development of MM.These tumors occur with high frequency on calvaria convexity, especially in the frontal region and skull base, including the sellar region.We found that long-term survival is conditional on post-operative management of RT and progression to MM.The precise role of aggressive tumor resection and CMT remains uncertain.Ki-67 index is a candidate for predicting the possibility of progression to MM. Future researches could endeavor to leverage advanced molecular biology techniques to promptly identify these high-risk individuals at diagnosis.Consequently, it is recommended to implement rigorous intracranial and general examinations within both neurosurgery and hematology departments, aiming to proactively impede the progression of intracranial plasmacytoma.It would provide some evidence for risk factors of intracranial plasmacytoma from this large cohort.

F I G U R E 2
Distribution of intracranial plasmacytomas.Skull base region mainly includes the sellar region, clivus, and jugular foramen.Calvarial convexity region includes the frontal, parietal, and orbital areas.Other regions include occipital, temporal, intraventricular, nasopharyngeal areas etc. Illustrations were created in Biorender.

F I G U R E 3
Survival analysis and multivariable analysis of the prognostic factors of MM-IPFP.(A) Kaplan-Meier survival curves of patients with MM-IPFP and SIP.(B-I) Kaplan-Meier survival curves of patients stratified by gender (B), surgical options (C), post-operative RT (D), tumor location (E), Ki-67 index (F), light chain staining (G and H) and dimensions of intracranial lesions (I) in MM-IPFP.(J) The multivariate Cox analysis for MM-IPFP.F I G U R E 4 Survival analysis and multivariable analysis of the prognostic factors of SIP.(A) Kaplan-Meier survival curves of all patients with SBP and EMP.(B-I) Kaplan-Meier survival curves of patients stratified by surgical options (B), post-operative treatments (C and D), tumor location (E), Ki-67 index (F), light chain staining (G and H) and dimensions of intracranial lesions (I) in SIP.(J) The multivariate Cox analysis for SIP.

F I G U R E 5
Clinicopathological differences between SIP with or without post-therapeutic progression.(A) Kaplan-Meier survival curves of SIPs with or without progression to MM. (B) Time interval of SBP and EMP progression.Blue circle points represent the time points of diagnosis.Green squares represent the time points of recurrence.Red triangles represent the time points of progression to MM. (C) Histogram demonstrating the fraction of patients with EMP and SBP progressing to MM (Fisher's exact test p-value = 0.02).(D) Histogram demonstrates the fraction of SIP patients with or without progression to MM receiving post-operative RT (Fisher's exact test p-value = 0.03).(E) Histogram demonstrates the fraction of SIP patients with or without progression to MM receiving post-operation CMT (Fisher's exact test p-value < 0.001).(F) Comparison of Ki-67 index between SIP, SIP with progression (including progression to MM and recurrence) and MM-IPFP.Unpaired t-test was used to calculate the p-values (SIP vs. progression, p-value = 0.018; SIP vs. MM-IPFP, p-value = 0.0003; progression vs. MM-IPFP, p-value = 0.078) (G) ROC curve for Ki-67 indexes in predicting SIP progression into MM.AUC = 0.712 with cutoff value of 9.0%.T A B L E 5 Genetic factors of patients with intracranial plasmacytoma.
Clinical characteristics of intracranial plasmacytoma.
T A B L E 1 The high rate of misdiagnosis complicates timely interventions and underscores the need for Abbreviations: CT, chemotherapy; CT, computed tomography; MM, multiple myeloma; MRI, magnetic resonance imaging; RT, radiotherapy.T A B L E 1(Continued) The univariate Cox analysis results for MM-IPFP group.The univariate Cox analysis results for SIP group.
T A B L E 2